Dihydroquinoline pyrazolyl compounds

ABSTRACT

The invention provides novel compounds having the general formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 15 , R 16 , R 17  and n are as described herein, compositions including the compounds and methods of using the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/EP2015/074774 having an international filing date of Oct. 26, 2015and which claims benefit under 35 U.S.C. §119 to InternationalApplication PCT/CN2014/090063 filed Oct. 31, 2014. The entire contentsof both are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel compounds of formula I, asdescribed herein, having pharmaceutical activity, their manufacture,pharmaceutical compositions containing them and their potential use asmedicaments.

BACKGROUND OF THE INVENTION

Herein we describe inhibitors of aldosterone synthase that have thepotential to protect from organ/tissue damage caused by an absolute orrelative excess of aldosterone. Hypertension affects about 20% of theadult population in developed countries. In persons 60 years and older,this percentage increases to above 60%. Hypertensive subjects display anincreased risk of other physiological complications including stroke,myocardial infarction, atrial fibrillation, heart failure, peripheralvascular disease and renal impairment. The renin angiotensin aldosteronesystem is a pathway that has been linked to hypertension, volume andsalt balance and more recently to contribute directly to end organdamage in advanced stages of heart failure or kidney disease. ACEinhibitors and angiotensin receptor blockers (ARBs) are successfullyused to improve duration and quality of life of patients. These drugsare not yielding maximum protection. In a relatively large number ofpatients ACE and ARB's lead to so-called aldosterone breakthrough, aphenomenon where aldosterone levels, after a first initial decline,return to pathological levels. It has been demonstrated that thedeleterious consequences of inappropriately increased aldosterone levels(in relation to salt intake/levels) can be minimized by aldosteroneblockade with mineralocorticoid receptor antagonists. A directinhibition of aldosterone synthesis is expected to provide even betterprotection as it will also reduce non-genomic effects of aldosterone aswell.

The effects of aldosterone on Na/K transport lead to increasedre-absorption of sodium and water and the secretion of potassium in thekidneys. Overall this results in increased blood volume and, therefore,increased blood pressure. Beyond its role in the regulation of renalsodium re-absorption aldosterone can exert deleterious effects on thekidney, the heart and the vascular system especially in a “high sodium”context. It has been shown that under such conditions aldosterone leadsto increased oxidative stress which ultimately may contribute to organdamage. Infusion of aldosterone into renally compromised rats (either byhigh salt treatment or by unilaterally nephrectomy) induces a wide arrayof injuries to the kidney including glomerular expansion, podocyteinjury, interstitial inflammation, mesangial cell proliferation andfibrosis reflected by proteinuria. More specifically aldosterone wasshown to increase the expression of the adhesion molecule ICAM-1 in thekidney. ICAM-1 is critically involved in glomerular inflammation.Similarly, aldosterone was shown to increase the expression ofinflammatory cytokines, such as interleukin IL-1b and IL-6, MCP-1 andosteopontin. On a cellular level it was demonstrated that in vascularfibroblasts aldosterone increased the expression of type I collagenmRNA, a mediator of fibrosis. Aldosterone also stimulates type IVcollagen accumulation in rat mesangial cells and induces plasminogenactivator inhibitor-1 (PAI-1) expression in smooth muscle cells. Insummary aldosterone has emerged as a key hormone involved in renaldamage. Aldosterone plays an equally important role in mediatingcardiovascular risk.

BRIEF SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula (I)

wherein

-   -   R¹, R⁵, R⁶, R⁷ and R⁸ are independently selected from H, alkyl,        haloalkyl, cycloalkyl and halocycloalkyl;    -   R², R³ and R⁴ are independently selected from H, halogen, alkyl,        haloalkyl, cycloalkyl and halocycloalkyl;

R⁹ is alkylsulfanylalkyl, alkyl sulfonylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,hetroarylalkyl, substituted heteroarylalkyl or the group A, whereinsubstituted aryl, substituted arylalkyl, substituted heteroaryl andsubstituted heteroarylalkyl are substituted with one to threesubstituents selected from alkyl, halogen, haloalkyl, cycloalkyl,halocycloalkyl, cyano, alkoxy, haloalkoxy, alkylsulfanyl,haloalkylsulfanyl, alkylsulfonyl and haloalkylsulfonyl;

-   -   R¹⁰ is pyrazolyl, substituted pyrazolyl, pyridinyl or        substituted pyridinyl, wherein substituted pyrazolyl and        substituted pyridinyl are substituted with one to three        substituents selected from alkyl, halogen, haloalkyl, cycloalkyl        and halocycloalkyl;    -   R¹⁵ is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl;    -   R¹⁶ and R¹⁷ are independently selected from H, alkyl and        cycloalkyl;    -   n is zero or 1;    -   and pharmaceutically acceptable salts thereof.

In another embodiment, the present inventions provide for pharmaceuticalcompositions comprising compounds of Formula I.

In another embodiment, the present invention provides aldosteronesynthase inhibitors for therapy in a mammal useful for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrome.

In another embodiment, the present invention provides aldosteronesynthase inhibitors for therapy in a mammal useful for the treatment ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrome.

DETAILED DESCRIPTION OF THE INVENTION

There is ample preclinical evidence that MR-antagonists (spironolactoneand eplerenone) improve blood pressure, cardiac and renal function invarious pre-clinical models.

More recently preclinical studies highlight the important contributionof CYP11B2 to cardiovascular and renal morbidity and mortality. TheCYP11B2 inhibitor FAD286 and the MR antagonist spironolactone wereevaluated in a rat model of chronic kidney disease (high angiotensin IIexposure; high salt and uni-nephrectomy). Angiotensin II and high salttreatment caused albuminuria, azotemia, renovascular hypertrophy,glomerular injury, increased PAI-1, and osteopontin mRNA expression, aswell as tubulointerstitial fibrosis. Both drugs prevented these renaleffects and attenuated cardiac and aortic medial hypertrophy. Following4 weeks of treatment with FAD286, plasma aldosterone was reduced,whereas spironolactone increased aldosterone at 4 and 8 weeks oftreatment. Similarly only spironolactone but not FAD286 enhancedangiotensin II and salt-stimulated PAI-1 mRNA expression in the aortaand the heart. In other studies the CYP11B2 inhibitor FAD286 improvedblood pressure and cardiovascular function and structure in rats withexperimental heart failure. In the same studies FAD286 was shown toimprove kidney function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, topatients with primary aldosteronism, lead to the conclusion that iteffectively inhibits CYP11B2 in patients with primary aldosteronismresulting in significantly lower circulating aldosterone levels and thatit corrected the hypokalemia and mildly decreased blood pressure. Theeffects on the glucocorticoid axis were consistent with a poorselectivity of the compound and a latent inhibition of cortisolsynthesis. Taken together these data support the concept that a CYP11B2inhibitor can lower inappropriately high aldosterone levels. Achievinggood selectivity against CYP11B1 is important to be free of undesiredside effects on the HPA axis and will differentiate different CYP11B2inhibitors.

The compounds of the present invention according formula (I) are potentinhibitors of

CYPB11B2 and present an improved selectivity towards CYP11B2 versusCYP11B1 combined with an improved metabolic stability.

Objects of the present invention are the compounds of formula (I) andtheir aforementioned salts and esters and their use as therapeuticallyactive substances, a process for the manufacture of the said compounds,intermediates, pharmaceutical compositions, medicaments containing thesaid compounds, their pharmaceutically acceptable salts or esters, theuse of the said compounds, salts or esters for the treatment orprophylaxis of illnesses, especially in the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrom and the use of the said compounds,salts or esters for the production of medicaments for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrom.

The term “alkoxy” denotes a group of the formula R′—O—, wherein R′ is analkyl group. Examples of alkoxy group include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particularalkoxy group include methoxy.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms. In particular embodiments,alkyl has 1 to 7 carbon atoms, and in more particular embodiments 1 to 4carbon atoms. Examples of alkyl include methyl, ethyl, propyl andisopropyl, n-butyl, iso-butyl, sec-butyl and ter-butyl. Particular alkylgroup is methyl.

The term “alkylsulfanyl” denotes a group of the formula R′—S—, whereinR′ is an alkyl group. Examples of alkylsulfanyl are groups wherein R′ ismethyl, ethyl, propyl and isopropyl, n-butyl, iso-butyl, sec-butyl andter-butyl. Particular alkylsulfanyl is group wherein R′ is methyl.

The term “alkylsulfanylalkyl” denotes an alkyl group wherein one of thehydrogen atoms of the alkyl group has been replaced an alkylsulfanylgroup. Particular examples of alkylsulfanylalkyl groups aremethylsulfanylethyl and methyl sulfanylpropanyl.

The term “alkylsulfonyl” denotes a group of the formula R′—S(O)₂—,wherein R′ is an alkyl group. Examples of alkylsulfonyl are groupswherein R′ is methyl, ethyl, propyl and isopropyl, n-butyl, iso-butyl,sec-butyl and ter-butyl. Particular alkylsulfonyl is group wherein R′ ismethyl.

The term “alkylsulfonylalkyl” denotes an alkyl group wherein one of thehydrogen atoms of the alkyl group has been replaced an alkylsulfonylgroup. Particular examples of alkylsulfanylalkyl group ismethylsulfonylethyl.

The term “aryl” denotes a monovalent aromatic carbocyclic mono- orbicyclic ring system comprising 6 to 10 carbon ring atoms. Examples ofaryl moieties include phenyl and naphthyl. Particular aryl group isphenyl.

The term “arylalkyl” denotes an alkyl group wherein one of the hydrogenatoms of the alkyl group has been replaced an aryl group. Particulararylalkyl group is phenylmethyl.

The term “cyano” denotes a —C≡T group.

The term “cycloalkyl” denotes a monovalent saturated monocyclichydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments, cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Examples for cycloalkylare cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.Particular cycloalkyl group is cyclopropyl.

The term “haloalkoxy” denotes an alkoxy group wherein at least one ofthe hydrogen atoms of the alkoxy group has been replaced by same ordifferent halogen atoms. The term “perhaloalkoxy” denotes an alkoxygroup where all hydrogen atoms of the alkoxy group have been replaced bythe same or different halogen atoms. Examples of haloalkoxy includefluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy,trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy.

The term “haloalkyl” denotes an alkyl group wherein at least one of thehydrogen atoms of the alkyl group has been replaced by the same ordifferent halogen atoms. The term “perhaloalkyl” denotes an alkyl groupwhere all hydrogen atoms of the alkyl group have been replaced by thesame or different halogen atoms. Examples of haloalkyl includefluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl,trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl group istrifluoromethyl.

The term “haloalkylsulfanyl” denotes a group of the formula —S—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfanyl groupsinclude groups of the formula —S—R′, wherein R′ is trifluoromethyl.

The term “haloalkylsulfonyl” denotes a group of the formula —S(O)₂—R′,wherein R′ is a haloalkyl group. Examples of haloalkylsulfonyl groupsinclude groups of the formula —S(O)₂—R′, wherein R′ is trifluoromethyl.

The term “halocycloalkyl” denotes a cycloalkyl group wherein at leastone of the hydrogen atoms of the cycloalkyl group has been replaced bysame or different halogen atoms, particularly fluoro atoms. Examples ofhalocycloalkyl include fluorocyclopropyl, difluorocyclopropyl,fluorocyclobutyl and difluorocyclobutyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo, or iodo. Particular halogens are chloro andfluoro. Particular halogen is fluoro.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl include pyrrolyl, furanyl, thienyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl,benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl,benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particularheteroaryl are imidazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrazolyl,pyridazinyl, pyrimidinyl, isoxazolyl. Particular heteroaryl is andpyrazolyl.

The term “heteroarylalkyl” denotes an alkyl group wherein one of thehydrogen atoms of the alkyl group has been replaced an aryl group.Particular heteroarylalkyl group is heteroarylmethyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be prepared byaddition of an inorganic base or an organic base to the free acid. Saltsderived from an inorganic base include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium salts and thelike. Salts derived from organic bases include, but are not limited tosalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.μAdditionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes the group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry. Protecting groups can be removed at the appropriatepoint. Exemplary protecting groups are amino-protecting groups,carboxy-protecting groups or hydroxy-protecting groups. Particularprotecting groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl(Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc). More particular protecting group is thetert-butoxycarbonyl (Boc).

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, but for the fact that one or moreatoms are replaced by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H (“T”), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P,³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I. Certain isotopically labeledcompounds of the present invention (e.g., those labeled with ³H or ¹⁴C)are useful in compound and/or substrate tissue distribution assays.Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resuting from greater metabolic stability (e.g., increased invivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present inventions can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting a non-isotopically labeledreagent with a isotopically labeled reagent. In particular, compounds offormula (I) wherein one or more H atom have been replaced by a ²H atomare also an embodiment of this invention.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention are compounds according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein wherein R¹ is alkyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R⁵, R⁶, R⁷ and R⁸ are H.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R² and R³ are H

Also an embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁴ is H or halogen.

A more particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R⁴ is H.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁵ is H.

Also a particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein R¹⁶ and R¹⁷ are H.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein n is 0.

Another particular embodiment of the present invention is are compoundsof formula (I) wherein R¹ is alkyl, R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁵, R¹⁶,and R¹⁷ are H, R⁴ is H or halogen and n is 0.

Another particular embodiment of the present invention are compoundsaccording to formula (I) as described herein, wherein the heteroarylgroup from R⁹ is alkylsulfanylalkyl, alkylsulfonylalkyl, substitutedaryl, substituted arylalkyl or the group A, wherein substituted aryl andsubstituted arylalkyl are substituted with one to three substituentsselected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl andalkylsulfonyl.

Another particular embodiment of the present invention is are compoundsof formula (I) wherein R¹ is alkyl, R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁵, R¹⁶,and R¹⁷ are H, R⁴ is H or halogen and n is 0 and wherein the heteroarylgroup from R⁹ is alkylsulfanylalkyl, alkylsulfonylalkyl, substitutedaryl, substituted arylalkyl or the group A, wherein substituted aryl andsubstituted arylalkyl are substituted with one to three substituentsselected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl andalkylsulfonyl.

Another embodiment of the present invention are compounds according toformula (I) as described herein, wherein R⁹ is aryl substituted with oneto three substituents selected from alkyl, halogen, cyano, alkoxy,alkylsulfanyl and alkylsulfonyl.

Another particular embodiment of the present invention is are compoundsof formula (I) wherein R¹ is alkyl, R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁵, R¹⁶,and R¹⁷ are H, R⁴ is H or halogen and n is 0 and wherein R⁹ is arylsubstituted with one to three substituents selected from alkyl, halogen,cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹² is pyrazolyl substitutedby alkyl.

A particular embodiment of the present invention are compounds accordingto formula (I) as described herein, wherein R¹⁰ is pyrazolyl substitutedby alkyl.

Another particular embodiment of the present invention is are compoundsof formula (I) wherein R¹ is alkyl, R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁵, R¹⁶ andR¹⁷are H, R⁴ is H or halogen and n is 0 and wherein R¹⁰ is pyrazolylsubstituted by one alkyl.

Another particular embodiment of the present invention is are compoundsof formula (I) wherein R¹ is alkyl, R², R³, R⁵, R⁶, R⁷, R⁸, R¹⁵, R¹⁶ andR¹⁷are H, R⁴ is H or halogen and n is 0 and wherein R¹⁰ is pyrazolylsubstituted by pyridinyl substituted by one halogen.

Particular examples of compounds of formula (I) as described herein areselected from

-   -   4-[[5-(1-Methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;    -   6-[4-(4-Chlorophenoxy)-1H-pyrazol-5-yl]-1-methyl-3,4-dihydroquinolin-2-one;    -   3-Methoxy-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;    -   3-Chloro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;    -   2-Fluoro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;    -   2-Chloro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;    -   6-[4-(3-Chlorophenoxy)-1H-pyrazol-5-yl]-1-methyl-3,4-dihydroquinolin-2-one;    -   1-Methyl-6-[4-(4-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;    -   1-Methyl-6-[4-(3-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;    -   1-Methyl-6-[4-(3-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;    -   1-Methyl-6-[4-(4-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;    -   1-Methyl-6-[4-(2-methylsulfanylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;    -   (rac)-1-Methyl-6-[4-(1-methylsulfanylpropan-2-yloxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;    -   1-Methyl-6-[4-(2-methyl        sulfonylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;    -   6-[4-[(4-Methoxyphenyl)methoxy]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;    -   6-[4-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;    -   5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;    -   and pharmaceutically acceptable salts thereof.

Processes for the manufacture of compounds of formula (I) as describedherein are an object of the invention.

The preparation of compounds of formula (I) of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following general schemes. The skillsrequired for carrying out the reaction and purification of the resultingproducts are known to those persons skilled in the art. In case amixture of enantiomers or diastereoisomers is produced during areaction, these enantiomers or diastereoisomers can be separated bymethods described herein or known to the persons skilled in the art suchas e.g. chiral chromatography or crystallization. The sub stituents andindices used in the following description of the processes have thesignificance given herein.

The following abbreviations are used in the present text:

AcOH=acetic acid, BOC=t-butyloxycarbonyl, BuLi=butyllithium,CDI=1,1-carbonyldiimidazole, DCM=dichloromethane,DBU=2,3,4,6,7,8,9,10-octahydro-pyrimido[1,2-a]azepine,DCE=1,2-dichloroethane, DIBALH=di-i-butylaluminium hydride,DCC=N,N′-dicyclohexylcarbodiimide, DMA=N,N-dimethylacetamide,DMAP=4-dimethylaminopyridine, DMF=N,N-dimethylformamide,EDCI=N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride,EtOAc=ethylacetate, EtOH=ethanol, Et₂O=diethylether, Et₃N=triethylamine,eq=equivalents,HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, HPLC=high performance liquid chromatography,HOBT=1-hydroxybenzo-triazole, Huenig's base=iPr₂NEt=N-ethyldiisopropylamine, IPC=in process control, LAH=lithium aluminium hydride,LDA=lithium diisopropylamide, LiBH₄=lithium borohydride, MeOH=methanol,NaBH₃CN, sodium cyanoborohydride, NaBH₄=sodium borohydride, NaI=sodiumiodide, Red-Al=sodium bis(2-methoxyethoxy) aluminium hydride, RT=roomtemperature, TBDMSCl=t-butyldimethylsilyl chloride, TFA=trifluoroaceticacid, THF=tetrahydrofuran, quant=quantitative.

Acetyl compounds 2 (Scheme 1) can be prepared from dihydro-quinolin-onecompounds 1 (known in the art or being prepared as described in Schemes5 and 6) by Friedel-Crafts alkylation (e.g. by treatment with acetylchloride, aluminum chloride in a solvent like carbon disulfide betweenroom temperature and reflux) (step a). Subsequent halogenation at theCH₃—CO moiety (e.g. by reaction with trimethylphenylammonium-tribromidein dichloromethane at room temperature) gives bromo-methyl compounds 3(step b). Reaction of bromo-methyl compounds 3 with suitablehydroxy-aryl or hydroxyl-heteroaryl compounds in the presence of a baselike sodium, potassium or cesium carbonate or sodium hydride in solventslike tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) attemperatures between room temperature and about 100° C. gives(hetero)-aryloxy ketones 4 (step c). (Hetero)-Aryloxy-ketones 4 reactwith 1,1-dimethoxy-N,N-dimethyl-methanamine in N,N-dimethylformamide attemperatures between about 50° C. and about 180° C. preferably withmicrowave heating to form dimethylamino adducts 5a or with a formic acidalkyl ester and a base like a sodium alkylate in an alcoholic solvent attemperatures between about 0° C. and room temperature to givehydroxy-alkene compounds 5b (step d). Dimethylamino adducts 5a orhydroxy-alkene compounds 5b react with hydrazine hydrate in the presenceof an acid like e.g. aqueous hydrochloric acid in solvents liketetrahydrofuran, dioxane, methanol, ethanol or mixtures thereof atelevated temperatures e.g. between about 50° C. and the refluxtemperature of the solvents to form pyrazole compounds 6 (step e).

Halo-pyrazole ester compounds 51 (Scheme 2) carrying a suitableprotecting group, as e.g. methoxybenzyl, tetrahydropyranyl,(2-trimethylsilyl)ethoxymethoxy, can be reduced to the correspondingprimary alcohols 52 (R¹⁶, R¹⁷=H), e.g. by using lithiumdiisobutylaluminium hydride in a solvent like tetrahydrofuran in atemperature range between about −78° C. and room temperature.Alternatively, halo-pyrazole ester compounds 51 can be transformed intosecondary or tertiary alcohols 52 by the following reaction sequence: i)saponification; ii) transformation into methoxy-N-methyl-amides (Weinrebamides); iii) conversion into ketones by reaction with Grignard reagentsR¹⁶MgX or lithium reagents R¹⁶Li in solvents like THF in a temperaturerange between −78° C. and room temperature; iv) reduction with lithiumdiisobutylaluminium hydride or with sodium borohydride or reaction withGrignard reagents R¹⁷MgX or lithium reagents R¹⁷Li in solvents like THFin a temperature range between −78° C. and room temperature (step a).

Haloalkyl compounds 53 can be obtained from hydroxy-alkyl compounds 52by transformation of the OH into e.g. a chloro or bromo function e.g. bytreatment with thionyl chloride or phosphorus tribromide in a solventlike DCM around room temperature, by reaction with methanesulfonylchloride, Et₃N or 2,4,6-trimethylpyridine, DCM or DMF, and optionallyLiCl or by reaction with triphenylphosphine/CCl₄ in CH₃CN, bothprocedures performed preferably between 0° C. and room temperature (stepb). Halo-alkyl derivatives 53 react with OH-substituted compounds 54 inthe presence of a base like sodium hydride or sodium or potassiumtert-butoxide, in a solvent like DMF or THF preferably in a temperaturerange between 0° C. and about 80° C. giving ether linked halo-pyrazolecompounds 55 (step c). Condensation of ether or amine linkedhalo-pyrazole compounds 55 with boronic acid or ester compounds 56(known in the art or being prepared as described in Schemes 5 and 6) canbe performed using Suzuki conditions, e.g. in the presence of catalysts,such as tri-o-tolylphosphine/palladium(II)acetate,tetrakis-(triphenylphosphine)-palladium,bis(triphenylphosphine)palladium(II)chloride ordichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) optionallyin the form of a dichloromethane complex (1:1), and in the presence of abase, such as aqueous or non aqueous potassium phosphate, sodium orpotassium carbonate, in a solvent, such as dimethylsulfoxide, toluene,ethanol, dioxane, tetrahydrofuran or N,N-dimethylformamide, and in aninert atmosphere such as argon or nitrogen, in a temperature rangepreferably between room temperature and about 130° C. leading topyrazoles 57 (steps d). Removal of the protecting group in pyrazoles 57then leads to pyrazoles 58 (e.g. treatment with trifluoroacetic acidunder microwave conditions at temperatures around 100° C. can be usedfor removal of a p-methoxy-benzyl protecting group, treatment with 4MHCl in dioxane in MeOH around room temperature can be used for removalof a THP protecting group) (step e).

Oxyalkyl pyrazoles 152 (Scheme 4), optionally carrying a protectinggroup, can be prepared from pyrazoles 151 by reaction with analkyl-halide, or an aralkyl-halide in a solvent like DMF in the presenceof a base like sodium hydride and optionally a catalyst liketetrabutylammonium iodide preferably between 0° C. and room temperature(step a).

Halogenation, e.g. iodination of oxyalkyl pyrazoles 152 (e.g. usingN-iodo succinimide in a solvent like DMF at elevated temperature (up to100° C.) gives halo-pyrazoles 153 (step b). Condensation ofhalo-pyrazoles 153 with boronic acid or ester compounds 56 can beperformed using Suzuki conditions as already described in Scheme 2 (stepc). Optional removal of the protecting group then leads to oxyalkylpyrazoles 155 (step d).

Chloropropionic acid anilides 201 (Scheme 5) can be prepared from chloropropionic acid chlorides and anilines 200 by reaction in a solvent likeDCM in the presence of a base like pyridine preferably around roomtemperature (step a). Chloropropionic acid anilides 201 undergo ringclosure to lactam compounds 202 when treated with AlCl₃ preferablywithout solvent at elevated temperatures of e.g. 100 to 150° C. (stepb). Lactam compounds 202 can be alkylated at nitrogen using a base likesodium hydride or sodium or potassium tert-butoxide, followed byaddition of an alkylating agent of formula wherein Y is halogen,tosylate or mesylate, in a solvent like DMF or THF preferably in atemperature range between 0° C. and about 80° C. giving N-alkylatedlactams 203 (step c). Optional halogenation of N-alkylated lactams 203can be performed e.g. by using N-bromo or N-chloro succinimide insolvents like DMF preferably around room temperature giving halo lactamcompounds 204 with X equal to bromine or chlorine respectively (step d).Reaction of lactams 204 with e.g.4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in solventslike dimethylsulfoxide or dioxane in the presence of potassium acetateand catalysts like(1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1complex with dichloromethane) at temperatures up to about 100° C. givesboronic ester compounds 56 (step e).

Treatment of nitro-benzene derivatives 250 e.g. with N-bromosuccinimide, benzoyl peroxide (BPO) in a solvent like CCl₄preferably atreflux gives bromo-methyl compounds 251 (Scheme 6, step a). Reaction ofbromo-methyl compounds 251 and a suitable malonic ester derivative,preferable in the presence of cesium carbonate in a solvent like DMFbetween 0° C. and room temperature gives malonic ester adducts 252 (stepb). Reduction of the nitro malonic ester derivatives 252 with e.g.stannous chloride dihydrate in 6 M aq. HCl at elevated temperature (e.g.130° C.) directly leads to lactam compounds 253 (step c). Lactamcompounds 253 can be alkylated at nitrogen, halogenated and convertedinto boronic ester compounds 256 as described for the preparation ofcompounds 56 (Scheme 5) (steps d, e, f).

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (II) in the presence of hydrazine hydrate;

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁵, R¹⁶, R¹⁷ are asdescribed herein and n is zero.

In particular, in the presence of an acid, in particular aqueoushydrochloric acid, in solvents like tetrahydrofuran, dioxane, methanol,ethanol or mixtures thereof at elevated temperatures, in particularbetween about 50° C. and the reflux temperature of the solvents.

Also an object of the present invention is a compound according toformula (I) as described herein for use as therapeutically activesubstance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I) as describedherein and a therapeutically inert carrier.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrom.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofdiabetic nephropathy.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofkidney or heart fibrosis.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofcongestive heart failure.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofhypertension.

The present invention also relates to the use of a compound according toformula (I) as described herein for the treatment or prophylaxis ofprimary aldosteronism.

A particular embodiment of the present invention is a compound accordingto formula (I) as described herein for the treatment or prophylaxis ofchronic kidney disease, congestive heart failure, hypertension, primaryaldosteronism and Cushing syndrom.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of diabetic nephropathy.

Another particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of kidney or heart fibrosis.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of chronic kidney disease.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of congestive heart failure.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of hypertension.

Also a particular embodiment of the present invention is a compoundaccording to formula (I) as described herein for the treatment orprophylaxis of primary aldosteronism.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of chronic kidney disease, congestive heartfailure, hypertension, primary aldosteronism and Cushing syndrom.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound according toformula (I) as described herein for the preparation of a medicament forthe treatment or prophylaxis of kidney or heart fibrosis.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of chronic kidney disease.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of congestive heart failure.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of hypertension.

Also an embodiment of the present invention is the use of a compoundaccording to formula (I) as described herein for the preparation of amedicament for the treatment or prophylaxis of primary aldosteronism.

Also an object of the invention is a method for the treatment orprophylaxis of chronic kidney disease, congestive heart failure,hypertension, primary aldosteronism and Cushing syndrom, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of diabetic nephropathy, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an object of the invention is a method for the treatment orprophylaxis of kidney or heart fibrosis, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of chronic kidney disease, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of congestive heart failure, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of hypertension, which method comprisesadministering an effective amount of a compound according to formula (I)as described herein.

Also an embodiment of the present invention is a method for thetreatment or prophylaxis of primary aldosteronism, which methodcomprises administering an effective amount of a compound according toformula (I) as described herein.

Also an embodiment of the present invention is a compound of formula (I)as described herein, when manufactured according to any one of thedescribed processes.

Assay Procedures

Herein we identified the use of the G-402 cell line as a host cell toectopically express (transiently or stably) enzymes of the CYP11 family.Specifically we developed stable G-402 cells expressing ectopicallyhuman CYP11B1, human CYP11B2, human CYP11A1, cynmolgus CYP11B1 orcynomolgus CYP11B2 enzyme activity. Importantly the identified cell lineG-402 expresses co-factors (adrenodoxin and adrenodoxin reductase)important for the activity of the CYP11 family and no relevant enzymeactivity of the CYP11 family (in comparison to H295R cells) was detectedin these cells. Therefore the G-402 cell line is uniquely suited as ahost cell for the ectopic expression of enzymes from the CYP11 family.

G-402 cells can be obtained from ATCC (CRL-1440) and were originallyderived from a renal leiomyoblastoma.

The expression plasmids contains the ORF for either human/cyno CYP11B1or CYP11B2 under the control of a suitable promoter (CMV-promoter) and asuitable resistance marker (neomycin). Using standard techniques theexpression plasmid is transfected into G-402 cells and these cells arethen selected for expressing the given resistance markers.

Individual cell-clones are then selected and assessed for displaying thedesired enzymatic activity using 11-Deoxycorticosterone (Cyp11B2) or11-Deoxycortisol (Cypl1B1) as a substrate.

G-402 cells expressing CYP11 constructs were established as describedabove and maintained in McCoy's 5a Medium Modified, ATCC Catalog No.30-2007 containing 10%

FCS and 400 pg/m1 G418 (Geneticin) at 37° C. under an atmosphere of 5%CO2/95% air. Cellular enzyme assays were performed in DMEM/F12 mediumcontaining 2.5% charcoal treated FCS and appropriate concentration ofsubstrate (0.3-10 uM 11-Deoxycorticosterone, 11-Deoxycortisol orCorticosterone). For assaying enzymatic activity, cells were plated onto96 well plates and incubated for 16h. An aliquot of the supernatant isthen transferred and analyzed for the concentration of the expectedproduct (Aldosterone for CYP11B2; Cortisol for CYP11B1). Theconcentrations of these steroids can be determined using HTRF assaysfrom CisBio analyzing either Aldosterone or Cortisol.

Inhibition of the release of produced steroids can be used as a measureof the respective enzyme inhibition by test compounds added during thecellular enzyme assay. The dose dependent inhibition of enzymaticactivity by a compound is calculated by means of plotting addedinhibitor concentrations (x-axes) vs. measured steroid/product level(y-axes). The inhibition is then calculated by fitting the following4-parameter sigmoidal function (Morgan-Mercer-Flodin (MMF) model) to theraw data points using the least squares method:

$y = \frac{{AB} + {Cx}^{D}}{B + x^{D}}$

wherein, A is the maximum y value, B is the EC50 factor determined usingXLFit, C is the minimum y value and D is the slope value.

The maximum value A corresponds to the amount of steroid produced in theabsence of an inhibitor, the value C corresponds to the amount ofsteroid detected when the enzyme is fully inhibited.

EC50 values for compounds claimed herein were tested with the G402-basedassay system described. Cyp11B2 enzyme activity was tested in presenceof 1 μM Deoxycorticosterone and variable amounts of inhibitors; Cyp11B1enzyme activity was tested in presence of 1 μM Deoxycortisol andvariable amounts of inhibitors.

EC50 EC50 human human CYP11B2 CYP11B1 Example nM nM 1 0.0133 0.8917 20.0155 0.3688 3 0.0943 1.6904 4 0.0403 2.7573 5 0.0581 0.7939 6 0.02461.1883 7 0.035 1.3932 8 0.0177 0.2975 9 0.0211 0.6635 10 0.06 4.0322 110.0197 0.652 12 0.0576 1.8512 13 0.1327 1.8098 14 0.502 22.1008 150.0017 0.0259 65 0.639 4.135 66 0.648 >30

Compounds of formula (I) and their pharmaceutically acceptable salts oresters thereof as described herein have EC₅₀ (CYP11B2) values between0.000001 uM and 1000 uM, particular compounds have EC₅₀ (CYP11B2) valuesbetween 0.00005 uM and 500 uM, further particular compounds have EC₅₀(CYP11B2) values between 0.0005 uM and 50 uM, more particular compoundshave EC₅₀ (CYP11B2) values between 0.0005 uM and 5 uM. These resultshave been obtained by using the described enzymatic assay.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays) or rectally(e.g. in the form of suppositories). However, the administration canalso be effected parentally, such as intramuscularly or intravenously(e.g. in the form of injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragées andhard gelatin capsules. Lactose, corn starch or derivatives thereof,talc, stearic acid or its salts etc. can be used, for example, as suchadjuvants for tablets, dragées and hard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should beappropriate. It will, however, be clear that the upper limit givenherein can be exceeded when this is shown to be indicated.

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of aldosterone mediated diseases.

The compounds of formula (I) or their pharmaceutically acceptable saltsand esters herein are inhibitiors of CYP11B2. The compounds of formula(I) or their pharmaceutically acceptable salts and esters herein displayalso variable inhibition of CYP11B1 but present an improved selectivitytowards CYP11B2 versus CYP11B1.. Such compounds may be used fortreatment or prophylaxis of conditions displaying excessive cortisolproduction/levels or both excessive cortisol and aldosterone levels (forex. Cushing syndrome, burn trauma patients, depression, post-traumaticstress disorders, chronic stress, corticotrophic adenomas, MorbusCushing).

In accordance with the invention, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of cardiovascular conditions (includinghypertension and heart failure), vascular conditions, endothelialdysfunction, baroreceptor dysfunction, renal conditions, liverconditions, fibrotic diseases, inflammatory conditions, retinopathy,neuropathy (such as peripheral neuropathy), pain, insulinopathy, edema,edematous conditions, depression and the like.

Cardiovascular conditions include congestive heart failure, coronaryheart disease, arrhythmia, arterial fibrillation, cardiac lesions,decreased ejection fraction, diastolic and systolic heart dysfunction,fibrinoid necrosis of coronary arteries, cardiac fibrosis, hypertrophiccardiomyopathy, impaired arterial compliance, impaired diastolicfilling, ischemia, left ventricular hypertrophy, myocardial and vascularfibrosis, myocardial infarction, myocardial necrotic lesions, cardiacarrhythmias, prevention of sudden cardiac death, restenosis, stroke,vascular damage.

Renal conditions include acute and chronic renal failure, nephropathy,end-stage renal disease, diabetic nephropathy, decreased creatinineclearance, decreased glomerular filtration rate, expansion ofreticulated mesangial matrix with or without significanthypercellularity, focal thrombosis of glomerular capillaries, globalfibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignantnephrosclerosis (such as ischemic retraction, microalbuminuria,proteinuria, reduced renal blood flow, renal arteriopathy, swelling andproliferation of intracapillary (endothelial and mesangial) and/orextracapillary cells (crescents).

Renal conditions also include glomerulonephritis (such as diffuseproliferative, focal proliferative, mesangial proliferative,membranoproliferative, minimal change membranous glomerulonephritis),lupus nephritis, non-immune basement membrane abnormalities (such asAlport syndrome), renal fibrosis and glomerulosclerosis (such as nodularor global and focal segmental glomerulosclerosis).

Liver conditions include, but are not limited to, liver steatosis,nonalcoholic steatohepatitis, liver cirrhosis, liver ascites, hepaticcongestionand the like.

Vascular conditions include, but are not limited to, thrombotic vasculardisease (such as mural fibrinoid necrosis, extravasation andfragmentation of red blood cells, and luminal and/or mural thrombosis),proliferative arteriopathy (such as swollen myointimal cells surroundedby mucinous extracellular matrix and nodular thickening),atherosclerosis, decreased vascular compliance (such as stiffness,reduced ventricular compliance and reduced vascular compliance),endothelial dysfunction, and the like.

Inflammatory conditions include, but are not limited to, arthritis (forexample, osteoarthritis), inflammatory airways diseases (for example,chronic obstructive pulmonary disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (forexample, arthralgia), and the like.

Edema includes, but is not limited to, peripheral tissue edema, hepaticcongestion, liver ascites, splenic congestion, respiratory or lungcongestion, and the like.

Insulinopathies include, but are not limited to, insulin resistance,Type I diabetes mellitus, Type II diabetes mellitus, glucosesensitivity, pre-diabetic state, pre-diabetes, syndrome X, and the like.

Fibrotic diseases include, but are not limited to myocardial andintrarenal fibrosis, renal interstitial fibrosis and liver fibrosis.

Furthermore, the compounds of formula (I) or their pharmaceuticallyacceptable salts and esters as described herein can also be used for thetreatment or prophylaxis of cardiovascular condition selected from thegroup consisting of hypertension, heart failure (particularly heartfailure post myocardial infarction), left ventricular hypertrophy, andstroke.

In another embodiment, the cardiovascular condition is hypertension.

In particular embodiment, the cardiovascular condition istreatment-resistant hypertension.

In another embodiment, the cardiovascular condition is heart failure.

In another embodiment, the cardiovascular condition is left ventricularhypertrophy.

In another embodiment, the cardiovascular condition is congestive heartfailure, more particularly in patients with preserved left ventricularejection fraction.

In another embodiment, the cardiovascular condition is stroke.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis renal condition.

In another embodiment, the renal condition is nephropathy.

In another embodiment, the renal condition is auto-immuneglomerulonephritis.

In another embodiment, the chronic kidney disease is diabeticnephropathy.

In another embodiment, the fibrotic disease is kidney or heart fibrosis.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis Type II diabetes mellitus.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis Type I diabetes mellitus.

In another embodiment, the compounds of formula (I) or theirpharmaceutically acceptable salts and esters can be used for thetreatment or prophylaxis of diabetic retinopathy.

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be separated by methods describedherein or by methods known to the persons skilled in the art, such ase.g. chiral chromatography or crystallization.

EXAMPLES

All examples and intermediates were prepared under argon atmosphere ifnot specified otherwise.

Pyrazoles carrying a hydrogen substituent at any of the two nitrogenatoms and not symmetrical substituents at the 3 carbon atoms alwaysexist in two tautomeric forms.

Formulas and names describe any of the two forms.

Intermediate A-1 4-[(Z and/orE)-2-(Dimethylamino)-1-(1-methyl-2-oxo-3,4-dihydroquinoline-6-carbonyl)vinyloxy]benzonitrile

[A]4-(2-(1-Methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxoethoxy)benzonitrile

To a solution of 6-(2-bromoacetyl)-1-methyl-3,4-dihydroquinolin-2-one(0.2 g, 0.709 mmol) in DMF (2 mL) was added 4-hydroxybenzonitrile (0.084g, 0.709 mmol) followed by K₂CO₃ (0.196 g, 1.42 mmol) and the reactionmixture was then stirred at room temperature for 2 h. The mixture wasdiluted with EtOAc, poured into 1N aqueous HCl solution (5 mL) and theaqueous layer was extracted with EtOAc (2×15 mL). The organic layerswere combined; the solid precipitate was filtered off and further driedto give a first batch of the title compound (0.135 g, 59%) as acolorless solid. The filtrate was dried over Na₂SO₄, filtered andevaporated. The residue was then purified by silica gel flashchromatography eluting with a 0 to 100% EtOAc-heptane gradient to give asecond batch of the title compound (0.075 g, 33%) as a colorless solid.MS: 321.5 (M+H⁺).

[B]4-[(Z and/orE)-2-(Dimethylamino)-1-(1-methyl-2-oxo-3,4-dihydroquinoline-6-carbonyl)vinyloxy]benzonitrile

In a microwave vial,4-(2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxoethoxy)benzonitrile(0.210 g, 0.656 mmol) and 1,1-dimethoxy-N,N-dimethyl-methanamine(DMF-DMA) (0.094 g, 0.787 mmol) were dissolved in DMF (1 mL) and thereaction mixture was then heated to 110° C. for 2 times 30 min undermicrowave irradiation. The mixture was evaporated to dryness and theresidue purified by silica gel flash chromatography eluting with a 0 to5% MeOH-dichloromethane gradient to give the title compound (0.216 g,88%) as a light brown solid. MS: 376.5 (M+H⁺).

Intermediate A-2(rac)-1-Methyl-6-[4-(2-methylsulfanylethoxymethyl)-1-tetrahydropyran-2-yl-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

[A] (rac)-Ethyl3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (0.4 g, 1.5mmol) in DCM (6 mL) was added 3,4-dihydro-2H-pyran (0.152 g, 1.8 mmol)followed by p-toluenesulfonic acid monohydrate (0.029 g, 0.15 mmol) andthe reaction mixture was then stirred at room temperature for 3 h. Themixture was diluted with DCM, poured into water (5 mL) and the aqueouslayer was extracted with EtOAc (2×20 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered and evaporated. Theresidue was then purified by silica gel flash chromatography elutingwith a 10 to 50% EtOAc-heptane gradient to give the title compound(0.526 g, 99%) as colorless oil.

[B] (rac)-(3-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol

To a solution of (rac)-ethyl3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carboxylate (0.526 g,1.5 mmol) in THF (5 mL) cooled to −78° C. was added a 1M DIBAL-Hsolution in THF (3 mL, 3 mmol) dropwise and the reaction mixture wasstirred at this temperature for 30 min. The mixture was then allowed toslowly warm up to 0° C. and stirring was continued at this temperaturefor 5 h. The mixture was quenched by drop wise addition of a 1N aqueousHCl solution (5 mL) and the resulting solution was then extracted withEtOAc (2×25 mL). The combined organics were washed with brine, driedover Na₂SO₄, filtered and evaporated. The residue was then purified bysilica gel flash chromatography eluting with a 0 to 100% EtOAc-heptanegradient to give the title compound (0.309 g, 67%) as colorless oil. MS:309.0 (M+H⁺).

[C](rac)-4-(Chloromethyl)-3-odo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a solution of(rac)-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methanol(0.309 g, 1.0 mmol) in DMF (3 mL) cooled to 0° C. were addedmethanesulfonyl chloride (0.172 g, 1.5 mmol) and 2,4,6-trimethylpyridine(0.194 g, 1.6 mmol). The reaction mixture was then stirred for 10 minbefore lithium chloride (0.085 g, 2.01 mmol) was added and stirring wascontinued at room temperature for 4 h. The mixture was diluted withEtOAc, poured into water (5 mL) and the aqueous layer was extracted withEtOAc (2×15 mL). The combined organics were washed with brine, driedover Na₂SO₄, filtered and evaporated. The residue was then purified bysilica gel flash chromatography eluting with a 0 to 70% EtOAc-heptanegradient to give the title compound (0.25 g, 75%) as colorless oil. MS:242.9 (M-THP+H⁺).

[D](rac)-3-Iodo-4-((2-(methylthio)ethoxy)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a suspension of NaH, 60% in mineral oil (0.006 g, 0.161 mmol), in DMF(0.5 mL) cooled to 0° C. was added 2-(methylthio)ethanol (0.014 g, 0.153mmol) and the reaction mixture was stirred for 30 min. Then,(rac)-4-(chloromethyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(0.05 g, 0.153 mmol) was added and stirring was continued at roomtemperature overnight. The mixture was diluted with EtOAc, poured into1N aqueous HCl solution (5 mL) and the aqueous layer was extracted withEtOAc (2×10 mL). The combined organics were washed with brine, driedover Na₂SO₄, filtered and evaporated. The residue was then purified bysilica gel flash chromatography eluting with a 0 to 50% EtOAc-heptanegradient to give the title compound (0.02 g, 34%) as colorless oil. MS:299.0 (M-THP+H⁺).

[E](rac)-1-Methyl-6-[4-(2-methylsulfanylethoxymethyl)-1-tetrahydropyran-2-yl-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

To a solution of(rac)-3-iodo-4-((2-(methylthio)ethoxy)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(0.02 g, 0.052 mmol) in DMF (0.5 mL) were added1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (0.015 g,0.052 mmol, Intermediate A-3),bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.004 g, 0.005mmol) and a 1M aqueous Na₂CO₃ solution (0.157 mL, 0.157 mmol). Thereaction mixture was then heated to 100° C. for 15 min under microwaveirradiation. The mixture was poured into water (2 mL) and extracted withEtOAc (2×5 mL). The combined organics were washed with brine, dried overNa₂SO₄, filtered and evaporated. The residue was purified by silica gelflash chromatography eluting with a 10 to 100% EtOAc-heptane gradient togive the title compound (0.015 g, 69%) as light brown oil. MS: 416.2(M+H⁺).

Intermediate A-31-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 6-Bromo-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (5 g, 22.1 mmol)in DMF (100 mL) cooled to 0° C. was added potassium tert-butoxide (4.96g, 44.2 mmol) portion wise and the reaction mixture was stirred at 0° C.for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and thereaction mixture allowed to warm up to room temperature and stirring wascontinued overnight. More methyl iodide (1.25 g, 8.86 mmol) was addedand the reaction mixture was heated to 40° C. until completion of thereaction. The mixture was diluted with EtOAc, poured into 100 mL of 1NHCl and the aqueous phase was extracted with EtOAc (2×200 mL). Thecombined organics were washed with brine, dried over anhy. Na₂SO₄,filtered and evaporated to dryness. The residue was purified by silicagel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradientto give the title compound (4.23 g, 80%) as an off white solid. MS:240.0, 242.1 (M+H⁻).

[B]1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

A flask was charged with 6-bromo-1-methyl-3,4-dihydroquinolin-2-one (3g, 12.5 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.81 g,15.0 mmol), potassium acetate (3.68 g, 37.5 mmol) and dioxane (48 mL).The mixture was purged with Ar, thendichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane complex (1:1) [PdCl₂(DPPF) dichloromethane adduct] (457mg, 0.560 mmol) was added and the resulting mixture was heated to 80° C.overnight. The reaction mixture was diluted with EtOAc, filtered throughCelite and washed with EtOAc (2×150 mL). The resulting filtrate waswashed with brine, dried over anhy. Na₂SO₄, filtered and evaporated todryness. The residue was purified by silica gel flash chromatographyeluting with a 0 to 40% EtOAc-heptane gradient to give the titlecompound (2.63 g, 73%) as an off white solid. MS: 288.0 (M+H⁺).

Intermediate A-47-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 3-Chloro-N-(3-fluoro-phenyl)-propionamide

To a solution of 3-fluoroanilline (10 mL, 104.02 mmol) in DCM (100 mL)was added pyridine (21 mL, 260.2 mmol) and 3-chloropropionyl chloride(12 mL, 124.4 mmol). The reaction mixture was stirred for 3 h at roomtemperature until all starting materials had disappeared as shown byLC-MS analysis. The reaction mixture was then diluted with H₂O andextracted with EtOAc. The organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo to afford the title compound as a solid. It wasused in the next step without further purification.

[B] 7-Fluoro-3,4-dihydro-1H-quinolin-2-one

A flame-dried 50-mL flask equipped with a magnetic stirring bar wascharged with 3-chloro-N-(3-fluoro-phenyl)-propionamide (10 g, 49.6 mmol)and AlCl₃ (23.1 g, 173.6 mmol). On a pre-heated oil bath, the flask washeated to 120˜125° C. for 2 h until LC-MS indicated the reaction wascomplete. After cooling to room temperature, the mixture was treatedslowly with ice-water. After extraction with EtOAc, combined organicswere washed with water and brine in sequence. The organic layer wasdried over anhy. Na₂SO₄, filtered and concentrated in vacuo to afford awhite solid (7.63 g, 93.2%).

[C] 7-Fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

To an ice cold solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (16.5g, 0.1 mol) in DMF (200 mL) was added potassium tert-butoxide (22.4 g,0.2 mol) in 2 portions. The reaction mixture was stirred at 0° C. for 30min before methyl iodide (25.4 g, 0.18 mol) was added. After theaddition, the reaction mixture was allowed to warm up to roomtemperature slowly and stirred at room temperature overnight. It wasthen diluted with EtOAc (500 mL) and poured into 200 mL of 1 N aq. HCl.After extraction with EtOAc (3×200 mL), the combined organics werewashed with brine, dried over anhy. Na₂SO₄, filtered and concentrated invacuo to give the crude title compound as oil (16.0 g, 89%). It was usedin the next step without further purification.

[D] 6-Bromo-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one

A mixture of 7-fluoro-1-methyl-3,4-dihydroquinolin-2-one (2.56 g, 0.014mol) and NBS (3.0 g, 0.017 mol) in DMF (30 mL) was stirred for 12 h at25° C. The reaction solution was diluted with H₂O (80 mL), and extractedwith EtOAc (3×100 mL). The combined organics were washed by brine (3×100mL), dried over anhy. Na₂SO₄ and concentrated in vacuo to give the titlecompound (1.5 g, 42%) as white foam. MS: 258.0, 259.9 (M+H⁺).

[E]7-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

In analogy to the procedure described for the preparation ofintermediates A-3[B],6-bromo-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one was reacted with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) in presenceof potassium acetate and PdCl₂(DPPF)-CH₂Cl₂ to give the title compoundas a white solid. MS: 306.1 (M+H⁺).

Intermediate A-58-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] N-(4-Bromo-2-chloro-phenyl)-3-chloro-propionamide

To a solution of 4-bromo-2-chloro-phenylamine (32 g, 0.15 mol) andpyridine (13.45 g, 0.17 mol) in DCM (200 mL) was added 3-chloropropionylchloride (21.65 g, 0.17 mol) dropwise at 15° C. After stirring at roomtemperature for 1 hour, the mixture was washed with water and thenaqueous 2N HCl. The organic layer was dried over anhy. Na₂SO₄, filtered,and concentrated in vacuo to afford title compound (10.9 g, 90%) as awhite solid.

[B] 6-Bromo-8-chloro-3,4-dihydro-1H-quinolin-2-one

A flame-dried 500-mL flask equipped with a magnetic stirring bar wascharged with N-(4-bromo-2-chloro-phenyl)-3-chloro-propionamide (29.7 g,0.1 mol) and aluminium chloride (53.3 g, 0.4 mol). In a pre-heated oilbath, the flask was heated to 140° C. for 1 h. After cooling to roomtemperature, the mixture was treated slowly with ice-water and extractedwith EtOAc. The organic layer was washed with water and brine insequence, dried over anhy. Na₂SO₄, filtered, and concentrated in vacuo.The resulting residue was then purified by silica gel flashchromatography (30% ethyl acetate in hexane) to afford the titlecompound (7.0 g, 27%) as a white solid.

[C] 6-Bromo-8-chloro-1-methyl-3,4-dihydro-1H-quinolin-2-one

A solution of 6-bromo-8-chloro-3,4-dihydro-1H-quinolin-2-one (7.0 g,26.9 mmol) in DMF (100 mL) was treated with potassium tert-butoxide (6.0g, 53.8 mmol) at 0° C. portion wise. The resulting mixture was stirredat 0° C. for 30 min before methyl iodide (5.0 g, 35.0 mmol) was added.After stirring for 12 h, the reaction mixture was treated with water,extracted with EtOAc. The organic layer was washed with water and brinein sequence, and dried over anhy. Na₂SO₄. After removal of solvent underreduced pressure, the crude product (3.3 g, 45%) was obtained as a whitesolid.

[D]8-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A mixture of 6-bromo-8-chloro-1-methyl-3,4-dihydro-1H-quinolin-2-one(0.23 g, 0.84 mmol), bis(pinacolato)diboron (0.255 g, 1.01mmol),1,1′-bis(diphenylphosphino)-ferrocene-dichloropalladium (II),dichloromethane complex (1:1) (30.7 mg, 0.04 mmol) and potassium acetate(0.247 g, 2.52 mmol) in dioxane (5 mL) was heated in a microwave at 80°C. overnight. After dilution with EtOAc, the organic layer was washedwith water, dried over anhy. Na₂SO₄ and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography (30% ethylacetate in hexane) to afford the title compound (0.17 g, 63%) as a whitesolid. MS: 322.2 (M+H⁻).

Intermediate A-65-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 2-(Bromomethyl)-1-fluoro-3-nitro-benzene

To a stirred solution of 1-fluoro-2-methyl-3-nitro-benzene (100 g, 0.64mol) and benzoyl peroxide (BPO) (15 g, 64 mmol) in CCl₄ (1500 mL) wasadded NBS (127 g, 0.73 mmol). The resulting reaction mixture was heatedto reflux for 12 h at 80° C. After TLC (PE: EA=20:1) indicated thecompletion of reaction, the reaction mixture was concentrated to removeCCl₄. The residue was diluted with DCM (500 mL), and washed with brine(2×300 mL). The organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo to give a crude title product (160 g, 80%). It wasused in the next step without further purification.

[B] Diethyl 2-[(2-fluoro-6-nitro-phenyl)methyl]propanedioate

To a stirred solution of NaH (26 g, 0.65 mol) in DMF (500 mL) was addeddiethyl malonate (106 g, 0.66 mol) in 200 mL of DMF at 0° C. It wasstirred for 30 min at 0° C. before adding a solution of2-(bromomethyl)-1-fluoro-3-nitro-benzene (128 g, 0.55 mol) in DMF (600mL). The mixture was then allowed to warm up to room temperature andstirring was continued for 3 h before quenching by the addition of satd.aq. NH₄Cl (500 mL). The mixture was diluted with H₂O (2 L), and theaqueous layer was extracted with EtOAc (3×800 mL). The combined organicswere washed with brine (3×500 mL), dried over anhy. Na₂SO₄ andconcentrated in vacuo to give a crude title product (180 g, 70%). It wasused in the next step without further purification.

[C] Ethyl 5-fluoro-2-oxo-3,4-dihydro-1H-quinoline-3-carboxylate

To a stirred solution of diethyl2-[(2-fluoro-6-nitro-phenyl)methyl]propanedioate (126 g, 0.4 mol) andNH₄Cl (103 g, 2.4 mol) in EtOH/H₂O (5:1, 1200 mL) was added iron powder(67 g, 1.2 mol) at 80° C. portion wise. The resulting mixture wasrefluxed for 2 h at 80° C. After cooling to room temperature, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give a crude title product (92 g, 50%). MS: 238.1 (M+H⁺). It was usedin the next step without further purification.

[D] 5-Fluoro-3,4-dihydro-1H-quinolin-2-one

A solution of ethyl5-fluoro-2-oxo-3,4-dihydro-1H-quinoline-3-carboxylate (46 g, 0.19 mol)in AcOH (300 mL) and HCl (150 mL) was heated to 90° C. for 1 h before itwas concentrated under reduced pressure. Saturated aqueous Na₂CO₃solution (500 mL) was carefully added to the residue, then it wasdiluted with additional H₂O (1 L), and extracted with EtOAc (3×300 mL).The combined organics were washed with brine (2×500 mL), dried overanhy. Na₂SO₄ and concentrated in vacuo to give a crude title product (28g, 89.3%). MS: 166.1 (M+H⁻). It was used in the next step withoutfurther purification.

[E] 5-Fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of NaH (8.1 g, 0.20 mol) in DMF (200 mL) was added5-fluoro-3,4-dihydro-1H-quinolin-2-one (28 g, 0.17 mol) in 100 mL of DMFat 0° C. The resulting reaction mixture was stirred at 0° C. for 10 minbefore methyl iodide (30 g, 0.21 mmol) was added. After the addition, itwas allowed to warm up to room temperature and stirred for 1 h. Thereaction was then quenched by the addition of satd. aq. NH₄Cl (200 mL),diluted with H₂O (1 L), and extracted with EtOAc (3×300 mL). Thecombined organics were washed with brine (3×500 mL), dried over anhy.Na₂SO₄ and concentrated in vacuo to give crude title compound (32 g,80%). MS: 180.1 (M+H⁻). It was used in the next step without furtherpurification.

[F] 6-Bromo-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-fluoro-1-methyl-3,4-dihydroquinolin-2-one (25.6 g,0.14 mol) in DMF (300 mL) was added NBS (30 g, 0.17 mol) and theresulting reaction mixture was stirred at room temperature for 12 h. Itwas diluted with H₂O (800 mL), and the aqueous layer was extracted withEtOAc (3×200 mL). The combined organics were washed with brine (3×300mL), dried over anhy. Na₂SO₄ and concentrated in vacuo to give crudetitle compound (15 g, 42%). MS: 256.1 and 258.1 (M+H⁺).

[G]5-Fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A flask was charged with6-bromo-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one (14.5 g, 56 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (28 g, 113mmol), potassium acetate (11 g, 113 mmol) and DMSO (300 mL). The mixturewas purged with Ar, thendichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II)dichloromethane complex (1:1) [PdCl₂(DPPF)-CH₂Cl₂ adduct] (2.2 g, 2.8mmol) was added and the resulting mixture was heated to 80° C. for 3 h.The reaction mixture was filtered and the filtrate was diluted withsatd. aq. NH₄Cl (200 mL) and H₂O (1 L). The aqueous layer was extractedwith EtOAc (3×200 mL) and the combined organics were washed with brine(2×200 mL), dried over anhy. Na₂SO₄, filtered and evaporated to dryness.The residue was purified by silica gel flash chromatography eluting witha 0 to 20% EtOAc-heptane gradient to give the desired title compound(7.9 g, 46.5%) as an off white solid. MS: 306.0 (M+H⁺).

Intermediate A-75-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2-one

[A] 2-(Bromomethyl)-1-chloro-3-nitro-benzene

A solution of 1-chloro-2-methyl-3-nitro-benzene (25.0 g, 145.7 mmol),N-bromosuccin-imide (30.0 g, 16.8 mmol) and benzoyl peroxide (2.5 g,10.4 mmol) in carbon tetrachloride (300 mL) was heated to 100° C. for 10h. After TLC indicated the reaction was completed, the reaction mixturewas filtered and the filtrate was concentrated in vacuo to give crudeproduct as yellow oil (40.0 g, 100%). MS: 250.1 (M+H)⁺. It was used inthe next step without further purification.

[B] Diethyl 2-[(2-chloro-6-nitro-phenyl)methyl]propanedioate

A solution of 2-(bromomethyl)-1-chloro-3-nitro-benzene (50.0 g, 199.6mmol), diethyl malonate (40.0 g, 260.0 mmol) and cesium carbonate (97.5g, 300.0 mmol) in DMF (550 mL) was stirred at 0° C. for 10 min and thenat room temperature for additional 2 h. The reaction was quenched by aq.1 N HCl (300 mL), and the aqueous layer was extracted with diethyl ether(3×500 mL). After filtration, the organic layer was dried over anhy.Na₂SO₄, and concentrated in vacuo to give crude compound as yellow oil(68.0 g, 100%). MS: 330.1 (M+H)⁺. It was used in the next step withoutfurther purification.

[C] 5-Chloro-3,4-dihydro-1H-quinolin-2-one

A solution of diethyl 2-[(2-chloro-6-nitro-phenyl)methyl]propanedioate(20 g, 61.9 mmol), stannous chloride dehydrate (100 g, 443.0 mmol) in 6Naq. HCl (400 mL) was heated to 130° C. for 5 h. The reaction mixturewas extracted with DCM (4×200 mL), and washed with brine. The organiclayer was dried over anhy. Na₂SO₄, filtered, and concentrated in vacuoto afford crude title compound as a yellow solid (18.0 g, 80%). MS:181.9 (M+H)⁺.

[D] 5-Chloro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-chloro-3,4-dihydro-1H-quinolin-2-one (16.0 g, 88.4mmol), t-BuONa (16.0 g, 166.7 mmol) in THF (200 mL) was added methyliodide (16.0 g, 140.4 mmol) drop wise at 0° C. After the addition, thereaction mixture was slowly warmed up to room temperature and stirredovernight. It was then quenched with satd. aq. NaCl solution, extractedwith diethyl ether (200 mL×3), dried over anhy. Na₂SO₄, and concentratedin vacuo. The residue was purified by silica gel flash chromatography toafford the desired title compound as a pale yellow solid (16.0 g, 82%).MS: 196.1 (M+H)⁺.

[E] 6-Bromo-5-chloro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-chloro-1-methyl-3,4-dihydroquinolin-2-one (15.2 g,77.6 mmol) in DMF (250 mL) was added bromosuccinimide (15.2 g, 85.4mmol) portion wise at 0° C. After the addition, the reaction mixture wasallowed to warm up to room temperature and stirred overnight. Thereaction was diluted with water (500 mL), extracted with diethyl ether(4×200 mL), dried over anhy. Na₂SO₄, and concentrated in vacuo. Theresidue was then purified by silica gel flash chromatography to affordthe desired title compound as a brown solid (16.0 g, 75%). MS: 274.9(M+H)⁺.

[F]5-Chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one

A stirred solution of6-bromo-5-chloro-1-methyl-3,4-dihydroquinolin-2-one (5.0 g, 18.2 mmol),bis(pinacolato)diboron (7.5 g, 29.5 mmol), PdCl₂(DPPF)-CH₂Cl₂ (1.0 g,1.23 mmol), KOAc (6.0 g, 61.2 mmol) in degassed dioxane (100 mL) andDMSO (10 mL) was heated to 90° C. overnight. After cooling to roomtemperature, the reaction mixture was filtered and the filtrate wasdiluted with diethyl ether, washed with brine, dried over anhy. Na₂SO₄,and concentrated in vacuo to give a crude product, which was thenpurified by silica gel flash chromatography to afford desired titlecompound as a white solid (2.8 g, 47%). MS: 322.2(M+H)⁺.

Intermediate A-10 5-Iodo-4-539 (4-methoxyphenyl)methoxy┐-1H-pyrazole

[A] 4-[(4-Methoxyphenyl)methoxy]-1H-pyrazole

To a solution of 1H-pyrazol-4-ol hydrochloride (1.00 g, 8.3 mmol) in DMF(20.0 mL) cooled to 0° C. were added tetrabutylammonium iodide (0.613 g,1.66 mmol), NaH 60% in mineral oil (0.995 g, 24.9 mmol) and the reactionmixture was stirred for 30 min. Then, 4-methoxybenzylbromide (1.67 g,8.3 mmol) was added drop wise to the mixture and stirring was continuedat 0° C. for 30 min. The reaction mixture was treated with a sat.aqueous NH₄Cl solution (10 mL) and extracted with EtOAc (3×50 mL). Thecombined organics were dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by silica gel flash chromatography, eluting with a5% to 100% EtOAc-heptane gradient to give the title compound (1.02 g,60%) as a colorless solid. MS: 205.1 (M+H⁺).

[B] 5-Iodo-4-[(4-methoxyphenyl)methoxy]-1H-pyrazole

To a solution of 4-(4-methoxybenzyloxy)-1H-pyrazole (1.02 g, 4.98 mmol)in DMF (15 mL) was added N-iodo-succinimide (1.23 g, 5.48 mmol) and thereaction mixture was heated to 60° C. for 2 h. The mixture was treatedwith H₂O (10 mL) and extracted with EtOAc (2×15 mL). The combinedorganics were dried over Na₂SO₄, filtered and evaporated. The residuewas purified by silica gel flash chromatography, eluting with a 10% to60% EtOAc-heptane gradient to give the title compound (1.11 g, 67.5%) asa colorless amorphous solid. MS: 331.0 (M+H⁺).

Intermediate A-11[3-Iodo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methanol

[A] Ethyl 3-iodo-1H-pyrazole-4-carboxylate

To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (40 g, 0.258mol) in MeCN (40 mL) was added isopentyl nitrite (36 g, 0.31 mol) andCH₂1₂ (207 g, 0.774 mol) at 0° C. The resulting mixture was stirred at0° C. for 20 min and then heated to 100° C. for 12 h. After cooling toroom temperature, the mixture was concentrated in vacuo and the residuewas diluted with water and extracted with EtOAc (3×300 mL). The combinedorganics were washed with brine (3×200 mL), dried over anhy. Na₂SO₄,filtered, and concentrated in vacuo to give a crude product, which waspurified by silica gel flash chromatography (PE: EA=2:1) to give thedesired title compound (40 g, 58%) as a yellow solid. MS: 267.1 (M+H⁺).

[B] Ethyl 3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

To a solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (40 g, 150 mmol)in THF (500 mL) was added NaH (7.2 g, 180 mmol) portion wise at 0° C.The resulting mixture was stirred at 0° C. for 30 min before SEMCl (30g, 180 mmol) was added drop wise. The mixture was then allowed to warmup to room temperature and stirred for 3 h before it was quenched withsatd. aq. NH₄Cl (200 mL), and extracted with EtOAc (3×200 mL). Thecombined organics were washed with brine (3×200 mL), dried over anhy.Na₂SO₄, filtered, and concentrated in vacuo to give a crude product,which was purified by silica gel flash chromatography (PE: EA=2:1) toafford the desired title compound (50 g, 84%) as a white solid. MS:397.1 (M+H⁺).

[C] [3-Iodo-1-(2-trimethyl silylethoxymethyl)pyrazol-4-yl]methanol

To a stirred solution of ethyl3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (50 g, 126mmol) in THF (600 mL) was added DIBAL (379 mL, 379 mmol) at −78° C. andthe resulting mixture was stirred at −78° C. for 3 h before was warmedup to room temperature and quenched by the addition of a satd. Seignettesalt solution (600 mL). After dilution with H₂O (1 L), the aqueous layerwas extracted with EtOAc (3×300 mL).

The combined organics were washed with brine (3×200 mL), dried overanhy. Na₂SO₄ filtered, and concentrated in vacuo to give a crudeproduct, which was purified by silica gel flash chromatography (PE:EA=2:1) to afford the desired title compound (28 g, 63%) as yellow oil.MS: 355.1 (M+H⁺).

Example 14-[[5-(1-Methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile

To a solution of 4-[(Z and/orE)-2-(dimethylamino)-1-(1-methyl-2-oxo-3,4-dihydroquinoline-6-carbonyl)vinyloxy]benzonitrile(intermediate A-1) (0.075 g, 0.2 mmol) in EtOH (2 mL) was addedhydrazine monohydrate (0.011 g, 0.22 mmol) followed by a 4M HCl indioxane solution (0.05 ml, 0.2 mmol) and the reaction mixture was thenheated to 80° C. overnight. The mixture was evaporated to dryness andthe residue purified by silica gel flash chromatography eluting with a 0to 5% MeOH-dichloromethane gradient to give the title compound (0.051 g,71%) as a light yellow solid. MS: 345.4 (M+H⁺).

The following examples listed in Table 1 were prepared from6-(2-bromoacetyl)-1-methyl-3,4-dihydroquinolin-2-one and a suitablephenol in analogy to the procedures described for the preparation ofintermediate A-1 and example 1:

TABLE 1 Name Reactant MS Example Aspect (phenol) (M + H⁺) 2

4-chloro- phenol 354.4 3

4-hydroxy- 3-methoxy- benzonitrile 375.6 4

3-chloro- 4-hydroxy- benzonitrile 379.6 5

2-fluoro- 4-hydroxy- benzonitrile 363.4 6

2-chloro- 4-hydroxy- benzonitrile 379.5 7

3-chloro-phenol 354.5 8

4-methylsulfanyl- phenol 366.5 9

3-methylsulfanyl- phenol 366.5

Example 101-Methyl-6-[4-(3-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-1-3,4-dihydroquinolin-2-one

Sodium bicarbonate (0.101 g, 1.2 mmol) in water (1 mL) was added at 0°C. (ice bath) to a solution of1-methyl-6-[4-(3-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one(example 9) (0.055 g, 0.150 mmol) in acetone (1 mL). A solution of oxone(0.13 g, 0.211 mmol) in water (1.5 mL) was added drop wise to themixture while keeping the temperature below 5° C. and stirring wascontinued at this temperature for 30 min and then at room temperaturefor 1 h. The mixture was quenched at 0° C. by addition of a 40% sodiumbisulfite solution (2 mL). The resulting suspension was diluted withEtOAc, acidified with a 25% aqueous HCl solution and the resultingaqueous layer was extracted with EtOAc (2×10 mL). The combined organicswere washed with brine, dried over Na₂SO₄, filtered and evaporated. Theresidue was purified by prep-HPLC (Gemini NX 3u column, gradient 1% aq.formic acid/acetonitrile) to give the title compound (0.03 g, 48%) as ayellow amorphous solid. MS: 398.5 (M+H⁺).

Example 111-Methyl-6-[4-(4-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one

In analogy to the procedure described in example 10,1-methyl-6-[4-(4-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one(example 8) has been oxidized with oxone to give the title compound as acolorless amorphous solid. MS: 398.6 (M+H⁺).

Example 121-Methyl-6-[4-(2-methylsulfanylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

To a solution of(rac)-1-methyl-6-[4-(2-methylsulfanylethoxymethyl)-1-tetrahydropyran-2-yl-pyrazol-3-yl]-3,4-dihydroquinolin-2-one(intermediate A-2) (0.015 g, 0.036 mmol) in MeOH (1 mL) was added a 4MHCl in dioxane solution (0.045 ml, 0.18 mmol) and the reaction mixturewas stirred at room temperature for 3 h. The mixture was evaporated todryness, the residue treated with a sat. NaHCO₃ solution (1 mL) and thenextracted with EtOAc (2×5 mL). The organic layers were dried overNa₂SO₄, filtered and evaporated to give the title compound (0.012 g,97%) as a light brown amorphous solid. MS: 332.2 (M+H⁺).

Example 13(rac)-1-Methyl-6-[4-(1-methylsulfanylpropan-2-yloxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

In analogy to the procedure described in example 12,1-methyl-6-[4-[(1-methyl-2-methylsulfanyl-ethoxy)methyl]-1-tetrahydropyran-2-yl-pyrazol-3-yl]-3,4-dihydroquinolin-2-one(as 2 racemic diastereomers) (prepared from(rac)-4-(chloromethyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole(intermediate A-2[C] and (rac)-1-methylsulfanylpropan-2-ol in analogy tothe procedures described for the preparation of intermediates A-2[D-E])has been treated with acid to give the title compound as a colorlessoil. MS: 346.2 (M+H⁺).

Example 141-Methyl-6-[4-(2-methylsulfonylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

In analogy to the procedure described in example 10,1-methyl-6-[4-(2-methylsulfanylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one(example 12) has been oxidized with oxone to give the title compound asan off-white amorphous solid. MS: 364.2 (M+H⁺).

Example 156-┌4-┌(4-Methoxyphenyl)methoxy┐-1H-pyrazol-3-yl┐-1-methyl-3,4-dihydroquinolin-2-one

To a solution of 5-iodo-4-[(4-methoxyphenyl)methoxy]-1H-pyrazole(intermediate A-10) (0.4 g, 1.21 mmol) in DMF (4 mL) were added1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one(0.348 g, 1.21 mmol), bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.085 g, 0.121 mmol) and a 1M aqueous Na₂CO₃ solution (3.64 mL,3.64 mmol). The reaction mixture was then heated to 120° C. for 1 hunder microwave irradiation. The mixture was poured into a sat. aqueousNaHCO₃ solution (2 mL) and extracted with EtOAc (2×10 mL). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andevaporated. The residue was purified by silica gel flash chromatographyeluting with a 10 to 100% EtOAc-heptane gradient to give the titlecompound (0.14 g, 30%) as a light yellow solid. MS: 364.2 (M+H⁺).

Example 656-[4-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

[A]2-[[4-(Bromomethyl)-3-iodo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

To a stirred solution of[3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methanol (2 g, 5.6mmol, intermediate A-11]) in DCM (30 mL) was added PBr₃ (750 mg, 2.8mmol) drop wise at 0° C. and stirring was continued for 1 h. Thereaction was then quenched by satd. aq. NaHCO₃ (20 mL), diluted with H₂O(50 mL), and extracted with DCM (3×10 mL). The combined organics werewashed with brine (2×20 mL), dried over anhy. Na₂SO₄, filtered, andconcentrated in vacuo to give a crude product (1.2 g, 41%). MS: 417.1(M+H⁺). It was used in the next step without further purification.

[B] tert-Butyl3-[[3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methoxy]azetidine-1-carboxylate

To a solution of NaH (110 mg, 2.8 mmol) in THF (20 mL) was addedtent-butyl 3-hydroxyazetidine-1-carboxylate (485 mg, 2.8 mmol) at 0° C.and it was stirred for 30 min before2-[[4-(bromomethyl)-3-iodo-pyrazol-1-yl]methoxy]ethyl-trimethyl-silane(1.2 g, 2.3 mmol) was added. This resulting mixture was allowed to warmup to room temperature and stirred overnight. The reaction was thenquenched by satd. aq. NH₄Cl (30 mL), diluted with H₂O (80 mL), andextracted with EtOAc (3×20 mL). The combined organics were washed withbrine (2×30 mL), dried over anhy. Na₂SO₄, filtered, and concentrated invacuo to give a crude product, which was purified by silica gel flashchromatography (PE: EA=2:1) to afford the desired title compound (0.8 g,68%) as yellow oil. MS: 510.1 (M+H⁺).

[C] tent-Butyl3-[[3-(5-fluoro-1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methoxy]azetidine-1-carboxylate

To a solution of tent-butyl3-[[3-iodo-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methoxy]azetidine-1-carboxylate(800 mg, 1.57 mmol), Cs₂CO₃ (1 g, 3.1 mmol) and5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one(478 mg, 1.57 mmol) (intermediate A-6) in dioxane/H₂O (15:1, 32 mL) wasadded PdCl₂(DPPF) (110 mg, 0.15 mmol) under N₂. The resulting solutionwas heated to 80° C. for 3 h. After cooling to room temperature, thereaction was quenched with satd. aq. NH₄Cl solution (40 mL), dilutedwith H₂O (50 mL), and extracted with EtOAc (3×20 mL). The combinedorganics were washed with brine (2×20 mL), dried over anhy. Na₂SO₄,filtered, and concentrated in vacuo to give a crude product, which waspurified by silica gel flash chromatography (DCM: MeOH=40:1) to affordthe desired title compound (680 mg, 77%) as yellow oil. MS: 561.2(M+H⁺).

[D]6-[4-(Azetidin-3-yloxymethyl)-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of tent-butyl3-[[3-(5-fluoro-1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methoxy]azetidine-1-carboxylate(680 mg, 1.2 mmol) in EtOAc (10 mL) was added 4 M HCl in EtOAc (5 mL) atroom temperature. The reaction mixture was stirred for 30 min before itwas concentrated in vacuo to give a crude product (560 mg, 93%). MS:461.2 (M+H⁺). It was used in the next step without further purification.

[E]6-[4-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

To a solution of6-[4-(azetidin-3-yloxymethyl)-1-(2-trimethylsilylethoxymethyl)-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one(200 mg, 0.43 mmol), EDCI (100 mg, 0.52 mmol) and HOBT (70 mg, 0.52mmol) in DCM (15 mL) was added 3-chloropyridine-2-carboxylic acid (67mg, 0.43 mmol) and DIPEA (110 mg, 0.86 mmol). The resulting reactionmixture was stirred at room temperature for 3 h before it was quenchedwith satd. aq. NH₄Cl (20 mL), diluted with H₂O (50 mL), and extractedwith DCM (3×10 mL). The combined organics were washed with brine (2×20mL), dried over anhy. Na₂SO₄, filtered, and concentrated in vacuo togive a crude product, which was purified by silica gel flashchromatography (DCM: MeOH=40:1) to afford the desired title compound(100 mg, 42%) as yellow oil. MS: 600.2 (M+H⁺).

[F]6-[4-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one

A solution of6-[4-[[1-(3-chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one(100 mg, 0.17 mmol) in TFA (10 mL) was stirred at room temperature for 1h. The reaction was quenched by satd. aq. NaHCO₃ solution (30 mL),diluted with H₂O (50 mL), and extracted with EtOAc (3×20 mL). Thecombined organics were washed with brine (2×20 mL), dried over anhy.Na₂SO₄, filtered, and concentrated in vacuo to give a crude product,which was purified by silica gel flash chromatography (DCM: MeOH=40: 1)to afford the desired title compound (35 mg, 45%) as yellow oil. MS:470.1 (M+H⁺).

Example 665-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

[A] 5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-3,4-dihydroquinolin-2-one

In analogy to the procedure described for the synthesis of example65[E], 1-methyl-pyrazole-4-carboxylic acid was used to give the desiredtitle compound (120 mg, 35%) as yellow oil. MS: 569.2 (M+H⁺).

[B]5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one

In analogy to the procedure described for the synthesis of Example65[F],5-fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1-(2-trimethylsilylethoxymethy)pyrazol-3-yl]-3,4-dihydroquinolin-2-onewas used to give the desired title compound (43 mg, 47%) as yellow oil.MS: 439.2 (M+H⁺).

Example A

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of tablets of the followingcomposition:

Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mgCorn starch  25 mg Talc  25 mg Hydroxypropylmethylcellulose  20 mg 425mg

Example B

A compound of formula (I) can be used in a manner known per se as theactive ingredient for the production of capsules of the followingcomposition:

Per capsule Active ingredient 100.0 mg Corn starch  20.0 mg Lactose 95.0 mg Talc  4.5 mg Magnesium stearate  0.5 mg 220.0 mg

We claim:
 1. A compound of formula (I)

wherein R¹, R⁵, R⁶, R⁷ and R⁸ are independently selected from H, alkyl,haloalkyl, cycloalkyl or halocycloalkyl; R², R³ and R⁴ are independentlyselected from H, halogen, alkyl, haloalkyl, cycloalkyl orhalocycloalkyl; R⁹ is alkylsulfanylalkyl, alkylsulfonylalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, hetroarylalkyl, substituted heteroarylalkyl orthe group A, wherein substituted aryl, substituted arylalkyl,substituted heteroaryl and substituted heteroarylalkyl are substitutedwith one to three sub stituents selected from the group consisting ofalkyl, halogen, haloalkyl, cycloalkyl, halocycloalkyl, cyano, alkoxy,haloalkoxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl andhaloalkylsulfonyl;

R¹⁰ is pyrazolyl, substituted pyrazolyl, pyridinyl or substitutedpyridinyl, wherein substituted pyrazolyl and substituted pyridinyl aresubstituted with one to three substituents selected from the groupconsisting of alkyl, halogen, haloalkyl, cycloalkyl and halocycloalkyl;R¹⁵ is H, alkyl, haloalkyl, cycloalkyl or halocycloalkyl; R¹⁶ and R¹⁷are independently selected from H, alkyl and cycloalkyl; n is zero or 1;or, pharmaceutically acceptable salts thereof.
 2. The compound accordingto claim 1, wherein R¹ is alkyl.
 3. The compound according to claim 1,wherein R⁵, R⁶, R⁷ and R⁸ are H.
 4. The compound according to claim 1wherein R² and R³ are H.
 5. The compound according to claim 1 wherein R⁴is H or halogen.
 6. The compound according to claim 1, wherein R⁴ is H.7. The compound according to claim 1 wherein R¹⁵ is H.
 8. The compoundaccording to claim 1, wherein R¹⁶ and R¹⁷ are H.
 9. The compoundaccording to claim 1 wherein n is
 0. 10. The compound according to claim1 wherein R¹ is alkyl, R², R³, R⁵, R⁶, R⁷, R8, R¹⁵, R¹⁶ and R¹⁷ are H,R⁴ is H or halogen and n is
 0. 11. The compound according to claim 10,wherein R⁹ is alkylsulfanylalkyl, alkylsulfonylalkyl, substituted aryl,substituted arylalkyl or the group A, wherein substituted aryl andsubstituted arylalkyl are substituted with one to three substituentsselected from alkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.
 12. The compound according to claim 1, wherein R⁹ isalkylsulfanylalkyl, alkylsulfonylalkyl, substituted aryl, substitutedarylalkyl or the group A, wherein substituted aryl and substitutedarylalkyl are substituted with one to three substituents selected fromalkyl, halogen, cyano, alkoxy, alkylsulfanyl and alkylsulfonyl.
 13. Thecompound according to claim 1 wherein R¹⁰ is either pyrazolylsubstituted by one alkyl or pyridinyl substituted by one halogen. 14.The compound of claim 11 wherein R⁹ is the group A and R¹⁰ is eitherpyrazolyl substituted by one alkyl or pyridinyl substituted by onehalogen.
 15. The compound according to claim 1 wherein R⁹ is arylsubstituted with one to three substituents selected from alkyl, halogen,cyano, alkoxy, alkylsulfanyl and alkyl sulfonyl.
 16. The compoundaccording to claim 11 wherein R⁹ is aryl substituted with one to threesubstituents selected from alkyl, halogen, cyano, alkoxy, alkylsulfanyland alkylsulfonyl.
 17. The compound according to claim 1, which compoundis selected from the group consisting of:4-[[5-(1-Methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;6-[4-(4-Chlorophenoxy)-1H-pyrazol-5-yl]-1-methyl-3,4-dihydroquinolin-2-one;3-Methoxy-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;3-Chloro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;2-Fluoro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;2-Chloro-4-[[5-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;6-[4-(3-Chlorophenoxy)-1H-pyrazol-5-yl]-1-methyl-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-(4-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-(3-methylsulfanylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-(3-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-(4-methylsulfonylphenoxy)-1H-pyrazol-5-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-(2-methylsulfanylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;(rac)-1-Methyl-6-[4-(1-methylsulfanylpropan-2-yloxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;1-Methyl-6-[4-(2-methylsulfonylethoxymethyl)-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;6-[4-[(4-Methoxyphenyl)methoxy]-1H-pyrazol-3-yl]-1-methyl-3,4-dihydroquinolin-2-one;6-[4-[[1-(3-Chloropyridine-2-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-5-fluoro-1-methyl-3,4-dihydroquinolin-2-one;and,5-Fluoro-1-methyl-6-[4-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]oxymethyl]-1H-pyrazol-3-yl]-3,4-dihydroquinolin-2-one;or, a pharmaceutically acceptable salt thereof.
 18. A process to preparea compound according to to claim 1 comprising the reaction of a compoundof formula (II) in the presence of hydrazine hydrate;


19. A pharmaceutical composition comprising a compound according toclaim 1 and at least one pharmaceutically acceptable carrier, diluent orexcipient.
 20. A method for the treatment chronic kidney disease,congestive heart failure, hypertension, primary aldosteronism andCushing syndrome, which method comprises administering to a patient inneed thereof, an effective amount of a compound according to claim 1.